Transcriptional regulation of neural stem cell expansion in adult hippocampus

  1. Nannan Guo
  2. Kelsey D McDermott
  3. Yu-Tzu Shih
  4. Haley Zanga
  5. Debolina Ghosh
  6. Charlotte Herber
  7. William R Meara
  8. James H Coleman
  9. Alexia Zagouras
  10. Lai Ping Wong
  11. Ruslan I Sadreyev
  12. J Tiago Gonçalves
  13. Amar Sahay  Is a corresponding author
  1. Massachusetts General Hospital, United States
  2. Albert Einstein College of Medicine, United States

Abstract

Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell-cycle, fatty acid oxidation and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

Data availability

Sequencing data have been deposited in GEO under accession code GSE164889.

The following data sets were generated

Article and author information

Author details

  1. Nannan Guo

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kelsey D McDermott

    Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yu-Tzu Shih

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Haley Zanga

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Debolina Ghosh

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Charlotte Herber

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. William R Meara

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. James H Coleman

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Alexia Zagouras

    Center for Regenerative Medicine, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0899-0910
  10. Lai Ping Wong

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Ruslan I Sadreyev

    Department of Molecular Biology, Massachusetts General Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. J Tiago Gonçalves

    Dominick Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Amar Sahay

    Center for Regenerative Medicine, Massachusetts, Massachusetts General Hospital, Boston, United States
    For correspondence
    asahay@mgh.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0677-1693

Funding

National Institute of Neurological Disorders and Stroke (R56NS117529)

  • J Tiago Gonçalves

National Institute of Neurological Disorders and Stroke (R56NS117529)

  • Amar Sahay

NA

Ethics

Animal experimentation: Animals were handled and experiments were conducted in accordance with procedures approved by the Institutional Animal Care and Use Committee (IACUC) at the Massachusetts General Hospital (2011N000084 ) and Albert Einstein College of Medicine in accordance with NIH guidelines.

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Publication history

  1. Preprint posted: July 14, 2021 (view preprint)
  2. Received: July 14, 2021
  3. Accepted: January 3, 2022
  4. Accepted Manuscript published: January 4, 2022 (version 1)
  5. Version of Record published: February 4, 2022 (version 2)

Copyright

© 2022, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,294
    Page views
  • 346
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Nannan Guo
  2. Kelsey D McDermott
  3. Yu-Tzu Shih
  4. Haley Zanga
  5. Debolina Ghosh
  6. Charlotte Herber
  7. William R Meara
  8. James H Coleman
  9. Alexia Zagouras
  10. Lai Ping Wong
  11. Ruslan I Sadreyev
  12. J Tiago Gonçalves
  13. Amar Sahay
(2022)
Transcriptional regulation of neural stem cell expansion in adult hippocampus
eLife 11:e72195.
https://doi.org/10.7554/eLife.72195
  1. Further reading

Further reading

    1. Computational and Systems Biology
    2. Neuroscience
    Andrew McKinney, Ming Hu ... Xiaolong Jiang
    Research Article

    The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multi-patch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multi-cell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell type-specific wiring principle that may be imposed by a unique chain-like rule.

    1. Neuroscience
    Ana Luisa de A. Marcelino, Owen Gray ... Tom Gilbertson
    Research Article

    Every decision that we make involves a conflict between exploiting our current knowledge of an action's value or exploring alternative courses of action that might lead to a better, or worse outcome. The sub-cortical nuclei that make up the basal ganglia have been proposed as a neural circuit that may contribute to resolving this explore-exploit 'dilemma'. To test this hypothesis, we examined the effects of neuromodulating the basal ganglia's output nucleus, the globus pallidus interna, in patients who had undergone deep brain stimulation (DBS) for isolated dystonia. Neuromodulation enhanced the number of exploratory choices to the lower value option in a 2-armed bandit probabilistic reversal-learning task. Enhanced exploration was explained by a reduction in the rate of evidence accumulation (drift rate) in a reinforcement learning drift diffusion model. We estimated the functional connectivity profile between the stimulating DBS electrode and the rest of the brain using a normative functional connectome derived from heathy controls. Variation in the extent of neuromodulation induced exploration between patients was associated with functional connectivity from the stimulation electrode site to a distributed brain functional network. We conclude that the basal ganglia's output nucleus, the globus pallidus interna, can adaptively modify decision choice when faced with the dilemma to explore or exploit.